EP2867227B1 - Modulatoren des komplementweges und verwendungen davon - Google Patents

Modulatoren des komplementweges und verwendungen davon Download PDF

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Publication number
EP2867227B1
EP2867227B1 EP13765776.3A EP13765776A EP2867227B1 EP 2867227 B1 EP2867227 B1 EP 2867227B1 EP 13765776 A EP13765776 A EP 13765776A EP 2867227 B1 EP2867227 B1 EP 2867227B1
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Prior art keywords
aza
bicyclo
carboxylic acid
amide
acetyl
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French (fr)
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EP2867227A2 (de
Inventor
Eva Altmann
Ulrich Hommel
Edwige Liliane Lorthiois
Juergen Klaus Maibaum
Nils Ostermann
Jean Quancard
Stefan Andreas Randl
Anna Vulpetti
Stefanie Flohr
Olivier Rogel
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Novartis AG
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Novartis AG
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    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the invention relates to the inhibition of the complement alternative pathway and particularly to inhibition of Factor D, in patients suffering from conditions and diseases associated with complement alternative pathway activation such as age-related macular degeneration, diabetic retinopathy and related ophthalmic diseases.
  • the complement system is a crucial component of the innate immunity system and comprises a group of proteins that are normally present in an inactive state. These proteins are organized in three activation pathways: the classical, the lectin, and the alternative pathways ( V. M. Holers, In Clinical Immunology: Principles and Practice, ed. R.R. Rich, Mosby Press; 1996, 363-391 ). Molecules from microorganisms, antibodies or cellular components can activate these pathways resulting in the formation of protease complexes known as the C3-convertase and the C5-convertase.
  • the classical pathway is a calcium/magnesium-dependent cascade, which is normally activated by the formation of antigen-antibody complexes.
  • the alternative pathway is a magnesium-dependent cascade which is activated by deposition and activation of C3 on certain susceptible surfaces (e.g., cell wall polysaccharides of yeast and bacteria, and certain biopolymer materials).
  • Factor D may be a suitable target for the inhibition of this amplification of the complement pathways because its plasma concentration in humans is very low (about 1.8 ⁇ g/mL), and it has been shown to be the limiting enzyme for activation of the alternative complement pathway ( P.H. Lesavre and H.J. Müller-Eberhard. J. Exp. Med., 1978; 148: 1498-1510 ; J.E. Volanakis et al., New Eng. J. Med., 1985; 312:395-401 ).
  • Macular degeneration is a clinical term that is used to describe a family of diseases that are characterized by a progressive loss of central vision associated with abnormalities of Bruch's membrane, the choroid, the neural retina and/or the retinal pigment epithelium.
  • the macula lutea In the center of the retina is the macula lutea, which is about 1/3 to 1 ⁇ 2 cm in diameter.
  • the macula provides detailed vision, particularly in the center (the fovea), because the cones are higher in density and because of the high ratio of ganlion cells to photoreceptor cells. Blood vessels, ganglion cells, inner nuclear layer and cells, and the plexiform layers are all displaced to the side (rather than resting above the photoreceptor cells), thereby allowing light a more direct path to the cones.
  • the choroid Under the retina is the choroid, a part of the uveal tract, and the retinal pigmented epithelium (RPE), which is between the neural retina and the choroid.
  • Age-related macular degeneration is associated with progressive loss of visual acuity in the central portion of the visual field, changes in color vision, and abnormal dark adaptation and sensitivity.
  • Two principal clinical manifestations of AMD have been described as the dry, or atrophic, form and the neovascular, or exudative, form.
  • the dry form is associated with atrophic cell death of the central retina or macula, which is required for fine vision used for activities such as reading, driving or recognizing faces.
  • About 10-20% of these AMD patients progress to the second form of AMD, known as neovascular AMD (also referred to as wet AMD).
  • Neovascular AMD is characterized by the abnormal growth of blood vessels under the macula and vascular leakage, resulting in displacement of the retina, hemorrhage and scarring. This results in a deterioration of sight over a period of weeks to years.
  • Neovascular AMD cases originate from intermediate or advanced dry AMD. The neovascular form accounts for 85% of legal blindness due to AMD. In neovascular AMD, as the abnormal blood vessels leak fluid and blood, scar tissue is formed that destroys the central retina.
  • CNV choroidal neovascularizaton
  • Complement factor H variant increases the risk of age-related macular degeneration. Science. 2005 Apr 15;308(5720):419-21 ; Klein RJ, et al Complement factor H polymorphism in age-related macular degeneration. Science. 2005 Apr 15;308(5720):385-9 ; Lau LI, et al. Association of the Y402H polymorphism in complement factor H gene and neovascular age-related macular degeneration in Chinese patients. Invest Ophthalmol Vis Sci. 2006 Aug;47(8):3242-6 ; Simonelli F, et al. Polymorphism p.402Y>H in the complement factor H protein is a risk factor for age related macular degeneration in an Italian population.Br J Ophthalmol.
  • D1 ( WO 2006/039252 ) discloses indole based compounds targeting CXCR 4 useful for treating conditions such as age related macular degeneration (AMD) but does not mention the compounds of the present invention.
  • D2 US 2012/004245
  • D3 WO 2010/066684
  • VEGF vascular endothelial growth factor
  • D4 ( WO 2012/093101 ) discloses indole compounds or analogues useful for the treatment of age-related macular degeneration but fails to disclose presently claimed compounds.
  • the present invention describes compounds that modulate, and preferably inhibit, activation of the alternative complement pathway. Moreover it describes compounds that modulate, and preferably inhibit, Factor D activity and/or Factor D mediated complement pathway activation.
  • Factor D modulators are preferably high affinity Factor D inhibitors that inhibit the catalytic activity of complement Factor Ds, such as primate Factor D and particularly human Factor D.
  • the compounds of the present invention inhibit or suppress the amplification of the complement system caused by C3 activation irrespective of the inital mechanism of activation (including for example activation of the classical, lectin or ficolin pathways).
  • complement mediated diseases include ophthalmic diseases (including early or neovascular age-related macular degeneration and geographic atrophy), autoimmune diseases (including arthritis, rheumatoid arthritis), Respiratory diseases, cardiovascular diseases.
  • ophthalmic diseases including early or neovascular age-related macular degeneration and geographic atrophy
  • autoimmune diseases including arthritis, rheumatoid arthritis
  • Respiratory diseases cardiovascular diseases.
  • the present invention provides compounds that modulate Factor D activation and/or Factor D-mediated signal transduction of the complement system.
  • Such compounds may be used in vitro or in vivo to modulate (preferably inhibit) Factor D activity in a variety of contexts.
  • a compound or salt thereof is provided in which the compound is selected from:
  • the invention provides a combination, in particular a pharmaceutical combination, comprising a therapeutically effective amount of the compound of the invention or any one of the specifically disclosed compounds of the invention and one or more therapeutically active agents (preferably selected from those listed infra ).
  • the term “isomers” refers to different compounds that have the same molecular formula but differ in arrangement and configuration of the atoms.
  • an optical isomer or “a stereoisomer” refers to any of the various stereo isomeric configurations which may exist for a given compound of the present invention and includes geometric isomers. It is understood that a substituent may be attached at a chiral center of a carbon atom. Therefore, the invention includes enantiomers, diastereomers or racemates of the compound.
  • “Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a “racemic" mixture.
  • the term is used to designate a racemic mixture where appropriate.
  • the asterisk (*) indicated in the name of a compound designate a racemic mixture.
  • "Diastereoisomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.
  • the absolute stereochemistry is specified according to the Cahn- Ingold- Prelog R-S system. When a compound is a pure enantiomer the stereochemistry at each chiral carbon may be specified by either R or S.
  • Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line.
  • Certain of the compounds described herein contain one or more asymmetric centers or axes and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as ( R )- or ( S )-.
  • the present invention is meant to include all such possible stereoisomers, including racemic mixtures, optically pure forms and intermediate mixtures.
  • Optically active ( R )- and ( S )- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans-configuration. All tautomeric forms are also intended to be included.
  • the term "pharmaceutically acceptable salts” refers to salts that retain the biological effectiveness and properties of the compounds of this invention and, which typically are not biologically or otherwise undesirable.
  • the compounds of the present invention are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids, e.g., acetate, aspartate, benzoate, besylate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfornate, chloride/hydrochloride, chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, , hydroiodide/iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate, mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/di
  • Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid.
  • Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
  • Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table.
  • the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.
  • Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like.
  • Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from a parent compound, a basic or acidic moiety, by conventional chemical methods.
  • such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid.
  • a stoichiometric amount of the appropriate base such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate
  • Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two.
  • use of non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable, where practicable.
  • any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds.
  • Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 F 31 P, 32 P, 35 S, 36 Cl, 125 I respectively.
  • isotopically labeled compounds as defined herein, for example those into which radioactive isotopes, such as 3 H, 13 C, and 14 C, are present.
  • Such isotopically labelled compounds are useful in metabolic studies (with 14 C), reaction kinetic studies (with, for example 2 H or 3 H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • an 18 F or labeled compound may be particularly desirable for PET or SPECT studies.
  • Isotopically labeled compounds can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
  • substitution with heavier isotopes, particularly deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements or an improvement in therapeutic index.
  • concentration of such a heavier isotope, specifically deuterium may be defined by the isotopic enrichment factor.
  • isotopic enrichment factor as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope.
  • a substituent in a compound of this invention is denoted deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).
  • Isotopically-labeled compounds can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagents in place of the non-labeled reagent previously employed.
  • solvates refers to a molecular complex of a compound of the present invention (including salts thereof) with one or more solvent molecules.
  • solvent molecules are those commonly used in the pharmaceutical art, which are known to be innocuous to a recipient, e.g., water, ethanol, dimethylsulfoxide, acetone and other common organic solvents.
  • hydrate refers to a molecular complex comprising a compound of the invention and water.
  • Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D 2 O, d 6 -acetone, d 6 -DMSO.
  • Compounds of the invention that contain groups capable of acting as donors and/or acceptors for hydrogen bonds may be capable of forming co-crystals with suitable co-crystal formers.
  • These co-crystals may be prepared by known co-crystal forming procedures. Such procedures include grinding, heating, co-subliming, co-melting, or contacting in solution compounds of the invention with the co-crystal former under crystallization conditions and isolating co-crystals thereby formed.
  • Suitable co-crystal formers include those described in WO 2004/078163 .
  • a therapeutically effective amount of a compound of the present invention refers to an amount of the compound of the present invention that will elicit the biological or medical response of a subject, for example, reduction or inhibition of an enzyme or a protein activity, or ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, etc.
  • a therapeutically effective amount refers to the amount of the compound of the present invention that, when administered to a subject, is effective to (1) at least partially alleviating, inhibiting, preventing and/or ameliorating a condition, or a disorder, or a disease or biological process (e.g., tissue regeneration and reproduction) (i) mediated by Factor D, or (ii) associated with Factor D activity, or (iii) characterized by activity (normal or abnormal) of the complement alternative pathway; or (2) reducing or inhibiting the activity of Factor D; or (3) reducing or inhibiting the expression of Factor D; or (4) reducing or inhibiting activation of the complement system and particularly reducing or inhibiting generation of C3a, iC3b, C5a or the membrane attack complex generated by activation of the complement alternative pathway.
  • a disease or biological process e.g., tissue regeneration and reproduction
  • a therapeutically effective amount refers to the amount of the compound of the present invention that, when administered to a cell, or a tissue, or a non-cellular biological material, or a medium, is effective to at least partially reducing or inhibiting the activity of Factor D and/or the complement alternative pathway; or at least partially reducing or inhibiting the expression of Factor D and/or the complement alternative pathway.
  • a therapeutically effective amount as illustrated in the above embodiment for Factor D and/or the complement alternative pathway.
  • the term "subject" refers to an animal. Typically the animal is a mammal. A subject also refers to for example, primates ( e . g ., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.
  • the term “inhibit”, “inhibition” or “inhibiting” refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.
  • the term “treat”, “treating” or “treatment” of any disease or disorder refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof).
  • “treat”, “treating” or “treatment” refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient.
  • “treat”, “treating” or “treatment” refers to modulating the disease or disorder, either physically, ( e . g ., stabilization of a discernible symptom), physiologically, ( e . g ., stabilization of a physical parameter), or both.
  • “treat”, “treating” or “treatment” refers to preventing or delaying the onset or development or progression of the disease or disorder.
  • a subject is "in need of” a treatment if such subject would benefit biologically, medically or in quality of life from such treatment.
  • any asymmetric atom (e.g., carbon) of the compound(s) of the present invention can be present in racemic or enantiomerically enriched, for example the ( R )-, ( S )- or ( R , S )- configuration.
  • each asymmetric atom has at least 50 % enantiomeric excess, at least 60 % enantiomeric excess, at least 70 % enantiomeric excess, at least 80 % enantiomeric excess, at least 90 % enantiomeric excess, at least 95 % enantiomeric excess, or at least 99 % enantiomeric excess in the ( R )- or ( S )- configuration.
  • Substituents at atoms with unsaturated bonds may, if possible, be present in cis- ( Z )- or trans- ( E )- form.
  • a compound of the present invention can be in the form of one of the possible stereoisomers, rotamers, atropisomers, tautomers or mixtures thereof, for example, as substantially pure geometric ( cis or trans ) isomers, diastereomers, optical isomers (antipodes), racemates or mixtures thereof.
  • Any resulting mixtures of isomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and/or fractional crystallization.
  • any resulting racemates of final products or intermediates can be resolved into the optical antipodes by known methods, e . g ., by separation of the diastereomeric salts thereof, obtained with an optically active acid or base, and liberating the optically active acidic or basic compound.
  • a basic moiety may thus be employed to resolve the compounds of the present invention into their optical antipodes, e . g ., by fractional crystallization of a salt formed with an optically active acid, e .
  • Racemic products can also be resolved by chiral chromatography, e . g ., high pressure liquid chromatography (HPLC) using a chiral adsorbent.
  • HPLC high pressure liquid chromatography
  • the compounds of the present invention may also form internal salts, e.g., zwitterionic molecules.
  • the compounds of the present invention can also be obtained in the form of their hydrates, or include other solvents used for their crystallization.
  • protecting group a readily removable group that is not a constituent of the particular desired end product of the compounds of the present invention.
  • the protection of functional groups by such protecting groups, the protecting groups themselves, and their cleavage reactions are described for example in standard reference works, such as J. F. W. McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973 , in T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", Third edition, Wiley, New York 1999 , in “ The Peptides”; Volume 3 (editors: E. Gross and J.
  • a characteristic of protecting groups is that they can be removed readily (i.e. without the occurrence of undesired secondary reactions) for example by solvolysis, reduction, photolysis or alternatively under physiological conditions ( e . g . by enzymatic cleavage).
  • Salts of compounds of the present invention having at least one salt-forming group may be prepared in a manner known to those skilled in the art.
  • salts of compounds of the present invention having acid groups may be formed, for example, by treating the compounds with metal compounds, such as alkali metal salts of suitable organic carboxylic acids, e.g. the sodium salt of 2-ethylhexanoic acid, with organic alkali metal or alkaline earth metal compounds, such as the corresponding hydroxides, carbonates or hydrogen carbonates, such as sodium or potassium hydroxide, carbonate or hydrogen carbonate, with corresponding calcium compounds or with ammonia or a suitable organic amine, stoichiometric amounts or only a small excess of the salt-forming agent preferably being used.
  • metal compounds such as alkali metal salts of suitable organic carboxylic acids, e.g. the sodium salt of 2-ethylhexanoic acid
  • organic alkali metal or alkaline earth metal compounds such as the corresponding hydroxides, carbonates or hydrogen carbonates
  • Acid addition salts of compounds of the present invention are obtained in customary manner, e . g . by treating the compounds with an acid or a suitable anion exchange reagent.
  • Internal salts of compounds of the present invention containing acid and basic salt-forming groups, e . g . a free carboxy group and a free amino group, may be formed, e . g . by the neutralisation of salts, such as acid addition salts, to the isoelectric point, e . g . with weak bases, or by treatment with ion exchangers.
  • Salts can be converted into the free compounds in accordance with methods known to those skilled in the art.
  • Metal and ammonium salts can be converted, for example, by treatment with suitable acids, and acid addition salts, for example, by treatment with a suitable basic agent.
  • diastereoisomers can be separated, for example, by partitioning between polyphasic solvent mixtures, recrystallisation and/or chromatographic separation, for example over silica gel or by e . g . medium pressure liquid chromatography over a reversed phase column, and racemates can be separated, for example, by the formation of salts with optically pure salt-forming reagents and separation of the mixture of diastereoisomers so obtainable, for example by means of fractional crystallisation, or by chromatography over optically active column materials.
  • mixtures of isomers that are formed can be separated into the individual isomers, for example diastereoisomers or enantiomers, or into any desired mixtures of isomers, for example racemates or mixtures of diastereoisomers, for example analogously to the methods described under "Additional process steps”.
  • solvents from which those solvents that are suitable for any particular reaction may be selected include those mentioned specifically or, for example, water, esters, such as lower alkyl-lower alkanoates, for example ethyl acetate, ethers, such as aliphatic ethers, for example diethyl ether, or cyclic ethers, for example tetrahydrofuran or dioxane, liquid aromatic hydrocarbons, such as benzene or toluene, alcohols, such as methanol, ethanol or 1- or 2-propanol, nitriles, such as acetonitrile, halogenated hydrocarbons, such as methylene chloride or chloroform, acid amides, such as dimethylformamide or dimethyl acetamide, bases, such as heterocyclic nitrogen bases, for example pyridine or N -methylpyrrolidin-2-one, carboxylic acid anhydrides, such as lower alkanoic acid anhydrides, for example acetic anhydride,
  • the compounds, including their salts, may also be obtained in the form of hydrates, or their crystals may, for example, include the solvent used for crystallization. Different crystalline forms may be present.
  • the compounds of the invention can be prepared according to the Schemes provided infra .
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition can be formulated for particular routes of administration such as oral administration, parenteral administration, and ophthalmic administration, etc.
  • the pharmaceutical compositions of the present invention can be made up in a solid form (including without limitation capsules, tablets, pills, granules, powders or suppositories), or in a liquid form (including without limitation solutions, suspensions, emulsions, each of which may be suitable for ophthalmic administration).
  • compositions can be subjected to conventional pharmaceutical operations such as sterilization and/or can contain conventional inert diluents, lubricating agents, or buffering agents, as well as adjuvants, such as preservatives, stabilizers, wetting agents, emulsifers and buffers, etc.
  • the pharmaceutical compositions are tablets or gelatin capsules comprising the active ingredient together with
  • Tablets may be either film coated or enteric coated according to methods known in the art.
  • compositions for oral administration include an effective amount of a compound of the invention in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use are prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets may contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients are, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate can be employed.
  • Formulations for oral use can be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil medium for example, peanut oil, liquid paraffin or olive oil.
  • compositions are aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions.
  • Said compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances.
  • Said compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1-75%, or contain about 1-50%, of the active ingredient.
  • compositions for transdermal application include an effective amount of a compound of the invention with a suitable carrier.
  • Carriers suitable for transdermal delivery include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host.
  • transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound of the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.
  • compositions for topical application include aqueous solutions, suspensions, ointments, creams, gels or sprayable formulations, e.g., for delivery by aerosol.
  • topical delivery systems will in particular be appropriate for ophthalmic application, e . g ., for the treatment of eye diseases e . g ., for therapeutic or prophylactic use in treating age related macular degeneration and other complement mediated ophthalmic disorders.
  • Such may contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
  • a topical application may also pertain to an inhalation or to an intranasal application. They may be conveniently delivered in the form of a dry powder (either alone, as a mixture, for example a dry blend with lactose, or a mixed component particle, for example with phospholipids) from a dry powder inhaler or an aerosol spray presentation from a pressurised container, pump, spray, atomizer or nebuliser, with or without the use of a suitable propellant.
  • a dry powder either alone, as a mixture, for example a dry blend with lactose, or a mixed component particle, for example with phospholipids
  • Dosage forms for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be desirable.
  • the ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body.
  • dosage forms can be made by dissolving or dispersing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the active compound in a polymer matrix or gel.
  • Ophthalmic formulations eye ointments, powders, solutions, are also contemplated as being within the scope of this invention.
  • the present invention further provides anhydrous pharmaceutical compositions and dosage forms comprising the compounds of the present invention as active ingredients, since water may facilitate the degradation of certain compounds.
  • Anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions.
  • An anhydrous pharmaceutical composition may be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions are packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers ( e . g ., vials), blister packs, and strip packs.
  • compositions and dosage forms that comprise one or more agents that reduce the rate by which the compound of the present invention as an active ingredient will decompose.
  • agents which are referred to herein as “stabilizers,” include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers, etc.
  • the compounds of the invention in free form or in pharmaceutically acceptable salt form exhibit valuable pharmacological properties, e.g. Factor D modulating properties, complement pathway modulating properties and modulation of the complement alternative pathway properties, e.g. as indicated in in vitro and in vivo tests as provided in the next sections and are therefore indicated for therapy.
  • pharmacological properties e.g. Factor D modulating properties, complement pathway modulating properties and modulation of the complement alternative pathway properties, e.g. as indicated in in vitro and in vivo tests as provided in the next sections and are therefore indicated for therapy.
  • the compound of the invention can be for use, inter alia , to prevent the onset of AMD, to prevent the progression of early AMD to advanced forms of AMD including neovascular AMD or geographic atrophy, to slow and/or prevent progression of geographic atrophy, to treat or prevent macular edema from AMD or other conditions (such as diabetic retinopathy, uveitis, or post surgical or non-surgical trauma), to prevent or reduce the loss of vision from AMD, and to improve vision lost due to pre-existing early or advanced AMD. It can also be for use in combination with anti-VEGF therapies in the treatment of neovascular AMD patients or for the prevention of neovascular AMD.
  • the compounds of the invention are suitable for use in the treatment of diseases and disorders associated with fatty acid metabolism, including obesity and other metabolic disorders.
  • the compounds of the invention may be for use in blood ampules, diagnostic kits and other equipment used in the collection and sampling of blood.
  • the use of the compounds of the invention in such diagnostic kits may inhibit the ex vivo activation of the complement pathway associated with blood sampling.
  • the pharmaceutical composition or combination of the present invention can be in unit dosage of about 1-1000 mg of active ingredient(s) for a subject of about 50-70 kg, or about 1-500 mg or about 1-250 mg or about 1-160 mg or about 0.5-100 mg, or about 1-50 mg of active ingredients.
  • the therapeutically effective dosage of a compound, the pharmaceutical composition, or the combinations thereof is dependent on the species of the subject, the body weight, age and individual condition, the disorder or disease or the severity thereof being treated. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each of the active ingredients necessary to prevent, treat or inhibit the progress of the disorder or disease.
  • the above-cited dosage properties are demonstrable in vitro and in vivo tests using advantageously mammals, e . g ., mice, rats, dogs, monkeys or isolated organs, tissues and preparations thereof.
  • the compounds of the present invention can be applied in vitro in the form of solutions, e . g ., aqueous solutions, and in vivo either enterally, parenterally, advantageously intravenously, e . g ., as a suspension or in aqueous solution.
  • the dosage in vitro may range between about 10 -3 molar and 10 -9 molar concentrations.
  • a therapeutically effective amount in vivo may range depending on the route of administration, between about 0.1-500 mg/kg, or between about 1-100 mg/kg.
  • the activity of a compound according to the present invention can be assessed by the following in vitro & in vivo methods.
  • the compound of the present invention may be administered either simultaneously with, or before or after, one or more other therapeutic agent.
  • the compound of the present invention may be administered separately, by the same or different route of administration, or together in the same pharmaceutical composition as the other agents.
  • the compound of the invention and the other therapeutic agent may be manufactured and/or formulated by the same or different manufacturers. Moreover, the compound of the invention and the other therapeutic may be brought together into a combination therapy: (i) prior to release of the combination product to physicians (e.g. in the case of a kit comprising the compound of the invention and the other therapeutic agent); (ii) by the physician themselves (or under the guidance of the physician) shortly before administration; (iii) in the patient themselves, e . g . during sequential administration of the compound of the invention and the other therapeutic agent.
  • the invention provides a compound of the invention for use in treating a disease or condition mediated by the complement alternative pathway, wherein the medicament is prepared for administration with another therapeutic agent.
  • the invention also provides another therapeutic agent for use in treating a disease or condition mediated by the complement alternative pathway, wherein the medicament is administered with a compound of the invention.
  • compositions can be administered alone or in combination with other molecules known to have a beneficial effect on retinal attachment or damaged retinal tissue, including molecules capable of tissue repair and regeneration and/or inhibiting inflammation.
  • useful, cofactors include anti-VEGF agents (such as an antibody or FAB against VEGF, e.g., Lucentis or Avastin), basic fibroblast growth factor (bFGF), ciliary neurotrophic factor (CNTF), axokine (a mutein of CNTF), leukemia inhibitory factor (LIF), neutrotrophin 3 (NT-3), neurotrophin-4 (NT-4), nerve growth factor (NGF), insulin-like growth factor II, prostaglandin E2, 30 kD survival factor, taurine, and vitamin A.
  • anti-VEGF agents such as an antibody or FAB against VEGF, e.g., Lucentis or Avastin
  • bFGF basic fibroblast growth factor
  • CNTF ciliary neurotrophic factor
  • axokine a mutein of
  • Suitable cofactors include symptom-alleviating cofactors, including antiseptics, antibiotics, antiviral and antifungal agents and analgesics and anesthetics.
  • Suitable agents for combination treatment with the compounds of the invention include agents known in the art that are able to modulate the activities of complement components.
  • a combination therapy regimen may be additive, or it may produce synergistic results (e . g ., reductions in complement pathway activity more than expected for the combined use of the two agents).
  • a combination therapy for preventing and/or treating autoimmune disease as described above with a compound of the invention and a B-Cell or T-Cell modulating agent for example cyclosporine or analogs thereof, rapamycin, RAD001 or analogs thereof.
  • a B-Cell or T-Cell modulating agent for example cyclosporine or analogs thereof, rapamycin, RAD001 or analogs thereof.
  • for multiple sclerosis therapy may include the combination of a compound of the invention and a second MS agent selected from fingolimod, cladribine, tysarbi, laquinimod, rebif, avonex.
  • the invention provides a compound of the invention for use as a medicament.
  • the invention provides a compound of the invention for use in the treatment of a disorder or disease in a subject mediated by complement activation.
  • the invention provides a compound of the invention for use in the treatment of a disorder or disease mediated by activation of the complement alternative pathway.
  • the invention provides the use of a compound of the invention in the manufacture of a medicament for the treatment of a disorder or disease in a subject characterized by activation of the complement system. More particularly in the manufacture of a medicament for the treatment of a disease or disorder in a subject characterized by over activiation of the complement alternative pathway.
  • the invention provides a compound of the invention for use in the treatment of a disorder or disease in a subject characterized by activation of the complement system. More particularly, described are uses of the compounds provided herein in the treatment of a disease or disorder characterized by over activiation of the complement alternative pathway or the C3 amplification loop of the alternative pathway. In certain embodiments, the use is in the treatment of a disease or disorder is selected from retinal diseases (such as age-related macular degeneration).
  • the present invention provides the compounds of the invention for use in treating a disease or disorder associated with increased complement activity by administering to a subject in need thereof an effective amount of the compounds of the invention.
  • uses are described for the treatment of diseases associated with increased activity of the C3 amplification loop of the complement pathway.
  • uses of treating or preventing compelment mediated diseases are described in which the complement activation is induced by antibody-antigen interactions, by a component of an autoimmune disease, or by ischemic damage.
  • the present invention provides the compounds of the invention for use in treating or preventing age-related macular degeneration (AMD).
  • AMD age-related macular degeneration
  • patients who are currently asymptomatic but are at risk of developing a symptomatic macular degeneration related disorder are suitable for administration with a compound of the invention.
  • the use in treating or preventing AMD include, but are not limited to, uses in treating or preventing one or more symptoms or aspects of AMD selected from formation of ocular drusen, inflammation of the eye or eye tissue, loss of photoreceptor cells, loss of vision (including loss of visual acuity or visual field), neovascularization (including CNV), retinal detachment, photoreceptor degeneration, RPE degeneration, retinal degeneration, chorioretinal degeneration, cone degeneration, retinal dysfunction, retinal damage in response to light exposure, damage of the Bruch's membrane, and/ or loss of RPE function.
  • the compound of the invention can be for use, inter alia , to prevent the onset of AMD, to prevent the progression of early AMD to advanced forms of AMD including neovascular AMD or geographic atrophy, to slow and/or prevent progression of geographic atrophy, to treat or prevent macular edema from AMD or other conditions (such as diabetic retinopathy, uveitis, or post surgical or non-surgical trauma), to prevent or reduce the loss of vision from AMD, and to improve vision lost due to pre-existing early or advanced AMD. It can also be for use in combination with anti-VEGF therapies in the treatment of neovascular AMD patients or in the prevention of neovascular AMD.
  • said disease or disorder is selected from uveitis, adult macuar degeneration, diabetic retinopathy, retinitis pigmentosa, macular edema, Behcet's uveitis,
  • complement related diseases or disorders include: neurological disorders, multiple sclerosis, stroke, Guillain Barre Syndrome, traumatic brain injury, Parkinson's disease, disorders of inappropriate or undesirable complement activation, hemodialysis complications, hyperacute allograft rejection, xenograft rejection, interleukin-2 induced toxicity during IL-2 therapy, inflammatory disorders, inflammation of autoimmune diseases, Crohn's disease, adult respiratory distress syndrome, thermal injury including burns or frostbite, myocarditis, post-ischemic reperfusion conditions, myocardial infarction, balloon angioplasty, post-pump syndrome in cardiopulmonary bypass or renal bypass, atherosclerosis, hemodialysis, renal ischemia, mesenteric artery reperfusion after aortic reconstruction, infectious disease or sepsis, immune complex disorders and autoimmune diseases, rheumatoid arthritis, systemic lupus erythematosus (SLE), SLE nephriti
  • lung disease and disorders such as dyspnea, hemoptysis, ARDS, asthma, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolisms and infarcts, pneumonia, fibrogenic dust diseases, inert dusts and minerals ( e . g ., silicon, coal dust, beryllium, and asbestos), pulmonary fibrosis, organic dust diseases, chemical injury (due to irritant gases and chemicals, e . g ., chlorine, phosgene, sulfur dioxide, hydrogen sulfide, nitrogen dioxide, ammonia, and hydrochloric acid), smoke injury, thermal injury ( e .
  • COPD chronic obstructive pulmonary disease
  • emphysema pulmonary embolisms and infarcts
  • fibrogenic dust diseases e e g ., silicon, coal dust, beryllium, and asbestos
  • pulmonary fibrosis e. fibrosis
  • organic dust diseases
  • the present invention provides the compounds of the invention for use in treating a complement related disease or disorder, wherein said disease or disorder is asthma, arthritis (e . g ., rheumatoid arthritis), autoimmune heart disease, multiple sclerosis, inflammatory bowel disease, ischemia-reperfusion injuries, Barraquer-Simons Syndrome, hemodialysis, systemic lupus, lupus erythematosus, psoriasis, multiple sclerosis, transplantation, diseases of the central nervous system such as Alzheimer's disease and other neurodegenerative conditions, atypicaly hemolytic uremic syndrome (aHUS), glomerulonephritis (including membrane proliferative glomerulonephritis), blistering cutaneous diseases (including bullous pemphigoid, pemphigus, and epidermolysis bullosa), ocular cicatrical pemphigoid or MPGN II.
  • asthma arthritis
  • arthritis e . g ., r
  • the present invention provides compounds of the invention for use in treating glomerulonephritis.
  • Symptoms of glomerulonephritis include, but not limited to, proteinuria; reduced glomerular filtration rate (GFR); serum electrolyte changes including azotemia (uremia, excessive blood urea nitrogen--BUN) and salt retention, leading to water retention resulting in hypertension and edema; hematuria and abnormal urinary sediments including red cell casts; hypoalbuminemia; hyperlipidemia; and lipiduria.
  • PNH paroxysmal nocturnal hemoglobinuria
  • the present invention provides the compounds of the invention for use in educing the dysfunction of the immune and/or hemostatic systems associated with extracorporeal circulation.
  • the compounds of the present invention can be for use in any procedure which involves circulating the patient's blood from a blood vessel of the patient, through a conduit, and back to a blood vessel of the patient, the conduit having a luminal surface comprising a material capable of causing at least one of complement activation, platelet activation, leukocyte activation, or platelet-leukocyte adhesion.
  • Such procedures include, but are not limited to, all forms of ECC, as well as procedures involving the introduction of an artificial or foreign organ, tissue, or vessel into the blood circuit of a patient. More particularly, such procedures include, but are not limited to, transplantation procedures including kidney, liver, lung or heart transplant procedures and islet cell transplant procedures.
  • Recombinant human factor D (expressed in E. coli and purified using standard methods) at 10 nM concentration is incubated with test compound at various concentrations for 1 hour at room temperature in 0.1 M Hepes buffer, pH 7.5, containing 1 mM MgCl 2 , 1 M NaCl and 0.05% CHAPS.
  • a synthetic substrate Z-Lys-thiobenzyl and 2,4-dinitrobenzenesulfonyl-fluoresceine are added to final concentrations of 200 ⁇ M and 25 ⁇ M, respectively.
  • the increase in fluorescence is recorded at excitation of 485 nm and emission at 535 nm in a microplate spectrofluorimeter.
  • IC 50 values are calculated from percentage of inhibition of complement factor D-activity as a function of test compound concentration.
  • Recombinant human factor D (expressed in E. coli and purified using standard methods) at a 10 nM concentration is incubated with test compound at various concentrations for 1 hour at room temperature in 0.1 M PBS pH 7.4 containing 7.5 mM MgCl 2 and 0.075% (w/v) CHAPS.
  • Cobra venom factor and human complement factor B substrate complex is added to a final concentration of 200 nM.
  • the enzyme reaction was stopped by addition of 0.1 M sodium carbonate buffer pH 9.0 containing 0.15 M NaCl and 40 mM EDTA.
  • the product of the reaction, Ba was quantified by means of an enzyme-linked-immunosorbent assay.
  • IC 50 values are calculated from percentage of inhibition of factor D-activity as a function of test compound concentration.
  • Phase separator Biotage - Isolute Phase separator (Part Nr: 120-1908-F for 70 mL and Part Nr: 120-1909-J for 150 mL)
  • TLC conditions R f values for TLC are measured on 5 x 10 cm TLC plates, silica gel F 254 , Merck, Darmstadt, Germany.
  • HPLC HPLC were performed using an Agilent 1100 or 1200 series instrument. Mass spectra and LC/MS were determined using an Agilent 1100 series instrument.
  • Part A Synthesis of substituted aromatic or heteroaromatic building blocks:
  • Triethylaluminum (21.7 mL, 40.4 mmol, 25 wt% solution in toluene) was added to a vigorously stirred solution of 5-bromo-1H-pyrazolo[3,4-c]pyridine [929617-35-6] (4.00 g, 20.2 mmol) and Pd(PPh 3 ) 4 (1.17 g, 1.01 mmol) in THF (100 mL) under argon.
  • the reaction mixture was stirred at 65°C for 60 h, cooled to RT and poured into sat. aq. NH 4 Cl.
  • the resulting suspension was filtered, the solid was washed with water and discarded. The filtrate and combined washings were extracted with EtOAc (3x).
  • Trimethylaluminum (23.9 mL, 47.8 mmol, 2M sol. in toluene) was added to a vigorously stirred solution of 7-chloro-1H-pyrazolo[3,4-c]pyridine (3.67 g, 23.9 mmol) and Pd(PPh 3 ) 4 (1.38 g, 1.19 mmol) in THF (109 mL) under argon.
  • the reaction mixture was stirred at 65°C for 16 h, cooled to RT and poured into sat. aq. NH 4 Cl.
  • the resulting suspension was filtered, the solid washed with water and discarded. The filtrate and the combined washings were extracted with EtOAc (3x).
  • the tilte compound was prepared as described for the synthesis of ( ⁇ )-trans-5-methoxy-3,3-dimethyl-cyclohexylamine hydrochloride in Scheme C4 step D and E starting from (( ⁇ )-cis-5-hydroxy-3,3-dimethyl-cyclohexyl)-carbamic acid tert-butyl ester (preparared as described in Scheme C4 step C).
  • MS UPLC/MS: 158.1 [M+H]+; t R (UPLC conditions h): 0.44 min.
  • Cis/trans relative stereochemistry was assigned based on NMR.
  • Dia 1 and Dia 2 display a trans relative stereochemistry
  • Dia 3 and Dia 4 display a cis relative stereochemistry.
  • the absolute stereochemistry of Dia 4: ((1R,3S)-3-trifluoromethyl-cyclohexyl)-carbamic acid benzyl ester was assigned by X-ray crystallography of Example 49 prepared from Dia 4.
  • Dia 3 is ((1S,3R)-3-trifluoromethyl-cyclohexyl)-carbamic acid benzyl ester.
  • Chloroiodomethane (440 ⁇ L, 6.06 mmol) was added at 0°C to a solution of (3-methylene-cyclohexyl)-carbamic acid tert-butyl ester (400 mg, 1.89 mmol) in dry DCE (6.3 mL) under an inerte atmosphere. Then, diethylzinc 1M in hexane (3.03 mL, 3.03 mmol) was added and the reaction mixture was stirred at RT for 3 h. The reaction mixture was poured into water and extracted several times with CH 2 Cl 2 .
  • Table 2 Example Structure Name Characterization (end-table notes); MS (LC/MS); t R (HPLC conditions) 16 (1R,3S,5R)-2-Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-1H-indol-3-yl)-amide] 3-(S)-cyclohex-2-enylamide 408 [M+H]+; t R (d): 3.79 min.
  • Example 36 (1R,3S,5R)-2- ⁇ 2-[3-Acetyl-5-(pyrimidin-2-ylmethoxy)-indazol-1-yl]-acetyl ⁇ -2-aza-bicyclo[3.1.0]hexane-3-carboxylic acid (2,2-difluoro-cyclohexyl)-amide- Dia 1
  • Example 37 (1R,3S,5R)-2- ⁇ 2-[3-acetyl-5-(pyrimidin-2-ylmethoxy)-indazol-1-yl]-acetyl ⁇ -2-aza-bicyclo[3.1.0]hexane-3-carboxylic acid (2,2-difluoro-cyclohexyl)-amide- Dia
  • Example 38 (1R,3S,5R)-2- ⁇ 2-[3-acetyl-5-(pyrimidin-2-ylmethoxy)-indazol-1-yl]-acetyl ⁇ -2-aza-bicyclo[3.
  • reaction mixture was stirred at RT for 16 h, frozen and lyophilized to afford a mixture of (1R,3S,5R)-2-aza-bicyclo[3.1.0]hexane-3-carboxylic acid (2,2-difluoro-cyclohexyl)-amide hydrochloride, MS: 245.1 [M+H]+ and (1R,3S,5R)-2-aza-bicyclo[3.1.0]hexane-3-carboxylic acid (2-fluoro-cyclohex-2-enyl)-amide hydrochloride, MS: 225.1 [M+H]+.
  • Example 36 (1R,3S,5R)-2- ⁇ 2-[3-Acetyl-5-(pyrimidin-2-ylmethoxy)-indazol-1-yl]-acetyl ⁇ -2-aza-bicyclo[3.1.0]hexane-3-carboxylic acid (2,2-difluoro-cyclohexyl)-amide - Dia 1
  • Example 37 (1R,3S,5R)-2- ⁇ 2-[3-Acetyl-5-(pyrimidin-2-ylmethoxy)-indazol-1-yl]-acetyl ⁇ -2-aza-bicyclo[3.1.0]hexane-3-carboxylic acid (2,2-difluoro-cyclohexyl)-amide - Dia 2
  • Example 38 (1R,3S,5R)-2- ⁇ 2-[3-acetyl-5-(pyrimidin-2-ylmethoxy)-indazol-1-yl]-acetyl ⁇ -2-aza-bicy
  • Example 39 1- ⁇ 2-[(1R,3S,5R)-3-(3-Methoxy-3-trifluoromethyl-cyclohexylcarbamoyl)-2-aza-bicyclo[3.1.0]hex-2-yl]-2-oxo-ethyl ⁇ -1H-indazole-3-carboxylic acid amide - Dia mix 1
  • the reaction mixture was stirred at RT for 7 h, poured into H 2 O and aq. HCl 0.1N and extracted with CH 2 Cl 2 (2x).
  • the combined extracts were washed with sat. aq. Na 2 CO 3 , dried (Na 2 SO 4 ), filtered, concentrated and the product was purified by preparative HPLC (Waters Sunfire C18 OBD, 5 ⁇ m, 30x100mm, flow 40 mL/min, eluent 5 to 100% CH 3 CN in H 2 O in 20 min, CH 3 CN and H 2 O containing 0.1% TFA).
  • the pure fractions were combined, poured into sat. aq. Na 2 CO 3 and extracted with CH 2 Cl 2 (2x).
  • Example 40 1- ⁇ 2-[(1R,3S,5R)-3-(3-Methoxy-3-trifluoromethyl-cyclohexylcarbamoyl)-2-aza-bicyclo[3.1.0]hex-2-yl]-2-oxo-ethyl ⁇ -1H-indazole-3-carboxylic acid amide - Dia mix 2
  • step A the mixture of diastereoisomers can be separated either in step A or C (for details, refer to Separation method section).
  • Example 110 1- ⁇ 2-[(1R,3S,5S)-3-(3,3-Dimethyl-cyclohexylcarbamoyl)-5-hydroxymethyl-2-aza-bicyclo[3.1.0]hex-2-yl]-2-oxo-thyl ⁇ -1H-indazole-3-carboxylic acid amide
  • Example 110 was prepared according to the general procedures described in Scheme D6 for the preparation of Example 110 from commercially available building blocks, if not. otherwise stated (see notes at the end of table 6) .
  • step A the mixture of diastereoisomers can be separated either in step A or C (for details, refer to Separation method section).
  • Table 6 Example Structure Name Characterization (end-table notes); MS (LC/MS); t R (HPLC conditions) 111 1- ⁇ 2-[(1R,3S,5S)-3-((R)-3,3-Dimethyl-cyclohexylcarbamoyl)-5-hydroxymethyl-2-aza-bicyclo[3.1.0]hex-2-yl]-2-oxo-ethyl ⁇ -1H-indazole-3-carboxylic acid amide (2[A6], 3[Method 17]); 485.4 [M+NH 4 ]+, 512.3 [M+HCOO]-; t R (d): 3.04 min.
  • Example 123 was prepared according to the general procedures described in Scheme D7 for the preparation of Example 123 from commercially available building blocks or Building blocks described in part C.
  • step A the mixture of diastereoisomers can be separated either in step A or C (for details, refer to Separation method section).
  • Example 56 prepared from Dia 2 was assigned by X-ray crystallography to 1- ⁇ 2-[(1R,3S,5R)-3-((R)-3,3-dimethyl-cyclohexylcarbamoyl)-2-aza-bicyclo[3.1.0]hex-2-yl]-2-oxo-ethyl ⁇ -1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid amide.
  • Example 55 the absolute stereochemistry of Example 55 was assigned to 1- ⁇ 2-[(1R,3S,5R)-3-((S)-3,3-dimethyl-cyclohexylcarbamoyl)-2-aza-bicyclo[3.1.0]hex-2-yl]-2-oxo-ethyl ⁇ -1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid amide.
  • Dia 2 was assigned to: (1R,3S,5R)-3-((R)-3,3-dimethyl-cyclohexylcarbamoyl)-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester and the absolute stereochemistry of Dia 1 to (1R,3S,5R)-3-((S)-3,3-dimethyl-cyclohexylcarbamoyl)-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester.
  • Example 23 and Example 24 prepared respectively from CIS-Dia 1 and CIS-Dia 2 were assigned based on biological data and comparison with Example 73 and Example 72. Based on these data, the absolute stereochemistry of CIS-Dia 1 was assigned to (1R,3S,5R)-3-((1R,3S)-3-ethyl-cyclohexylcarbamoyl)-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester and CIS-Dia 2 to: (1R,3S,5R)-3-((1S,3R)-3-ethyl-cyclohexylcarbamoyl)-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester.
  • Example 73 The absolute stereochemistry of Example 73 was assigned based on X-ray crystallography to: 1- ⁇ 2-[(1R,3S,5R)-3-((1R,3S)-3-ethyl-cyclohexylcarbamoyl)-2-aza-bicyclo[3.1.0]hex-2-yl]-2-oxoethyl ⁇ -1H-pyrazolo[3,4-c] pyridine-3-carboxylic acid amide.
  • Example 72 the absolute stereochemistry of Example 72 was attributed to: 1- ⁇ 2-[(1R,3S,5R)-3-((1S,3R)-3-ethyl-cyclohexylcarbamoyl)-2-aza-bicyclo[3.1.0]hex-2-yl]-2-oxo-ethyl ⁇ -1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid amide.
  • Cis/trans relative stereochemistry was assigned based on NMR. Dia 1 and Dia 2 display a trans relative stereochemistry, Dia 3 and Dia 4 display a cis relative stereochemistry.
  • the absolute stereochemistry of Example 47 was assigned by X-ray crystallography to: 1- ⁇ 2-[(1R,3S,5R)-3-((1R,3S)-3-methyl-cyclohexylcarbamoyl)-2-aza-bicyclo[3.1.0]hex-2-yl]-2-oxo-ethyl ⁇ -1H-indazole-3-carboxylic acid amide.
  • Cis Dia 4 The absolute stereochemistry of Cis Dia 4 was assigned to (1R,3S,5R)-3-((1R,3S)-3-methyl-cyclohexylcarbamoyl)-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester and Cis Dia 3 vice versa was assigned to (1R,3S,5R)-3-((1S,3R)-3-methyl-cyclohexylcarbamoyl)-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester.
  • Example 70 prepared from Dia 1 and Example 71 prepared from Dia 2 was assigned based on biological data and in comparison with Example 56. Based on these data, the absolute stereochemistry of Dia 1 was assigned to (2S,4R)-2-((S)-3,3-dimethyl-cyclohexylcarbamoyl)-4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester and vice versa Dia 2 to: (2S,4R)-2-((R)-3,3-dimethyl-cyclohexylcarbamoyl)-4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester.

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Claims (6)

  1. Verbindung oder Salz davon, ausgewählt aus der Gruppe bestehend aus
    (1R,3S,5R)-2-[2-(3-Acetylpyrazolo[3,4-c]pyridin-1-yl)acetyl]-2-azabicyclo[3.1.0]hexan-3-carbonsäure-(3,3-dimethylcyclobutyl) amid,
    (1R,3S,5R)-2-[2-(3-Acetylpyrazolo[3,4-b]pyridin-1-yl)acetyl]-2-azabicyclo[3.1.0]hexan-3-carbonsäure-(2,2-dimethylcyclopropyl) amid,
    (1R,3S,5R)-2-[2-(3-Acetylpyrazolo[3,4-b]pyridin-1-yl)acetyl]-2-azabicyclo[3.1.0]hexan-3-carbonsäure-(2,2-difluorcyclopropyl) amid,
    (1R,3S,5R)-2-[2-(3-Acetylpyrazolo[3,4-b]pyridin-1-yl)acetyl]-2-azabicyclo[3.1.0]hexan-3-carbonsäure-((1R,2S)-2-fluorcyclopropyl)amid,
    (1R,3S,5R)-2-[2-(3-Acetylpyrazolo[3,4-b]pyridin-1-yl)acetyl]-2-azabicyclo[3.1.0]hexan-3-carbonsäure-(3,3,5-trimethylcyclohexyl)amid,
    (1R,3S,5R)-2-[2-(3-Acetylpyrazolo[3,4-b]pyridin-1-yl)acetyl]-2-azabicyclo[3.1.0]hexan-3-carbonsäure-(3, 3, 5, 5-tetramethylcyclohexyl)amid,
    (1R,3S,5R)-2-[2-(3-Acetylpyrazolo[3,4-c]pyridin-1-yl)acetyl]-2-azabicyclo[3.1.0]hexan-3-carbonsäure-(2,2-dimethyltetrahydropyran-4-yl)amid,
    (1R,3S,5R)-2-[2-(3-Acetylpyrazolo[3,4-c]pyridin-1-yl)acetyl]-2-azabicyclo[3.1.0]hexan-3-carbonsäure-(3,3-difluorcyclobutyl)amid,
    (1R,3S,5R)-2-[2-(3-Acetylpyrazolo[3,4-c]pyridin-1-yl)acetyl]-2-azabicyclo[3.1.0]hexan-3-carbonsäure-(3,3-difluorcyclohexyl)amid,
    (1R,3S,5R)-2-[2-(3-Acetypyrazolo[3,4-c]pyridin-1-yl)acetyl]-2-azabicyclo[3.1.0]hexan-3-carbonsäure-(1-hydroxymethylcyclohexyl)amid,
    (1R,3S,5R)-2-[2-(3-Acetylpyrazolo[3,4-c]pyridin-1-yl)acetyl]-2-azabicyclo[3.1.0]hexan-3-carbonsäure-(4,4-difluorcyclohexyl)amid,
    (1R,3S,5R)-2-[2-(3-Acetylpyrazolo[3,4-b]pyridin-1-yl)acetyl]-2-azabicyclo[3.1.0]hexan-3-carbonsäure-((1R,3R)-3-carbamoylcyclopentyl)amid,
    (1R,3R)-3-({(1R,3S,5R)-2-[2-(3-Acetylpyrazolo[3,4-b]pyridin-1-yl)acetyl]-2-azabicyclo[3.1.0]hexan-3-carbonyl}amino)cyclopentancarbonsäuremethylester,
    (1R,3S)-3-({(1R,3S,5R)-2-[2-(3-Acetylpyrazolo[3,4-b]pyridin-1-yl)acetyl]-2-azabicyclo[3.1.0]hexan-3-carbonyl}amino)cyclohexancarbonsäuremethylester,
    (1R,3S,5R)-2-Azabicyclo[3.1.0]hexan-2,3-dicarbonsäure-2-[(1-carbamoyl-1H-indol-3-yl)amid]-3-cyclohexylamid,
    (1R,3S,5R)-2-Azabicyclo[3.1.0]hexan-2,3-dicarbonsäure-2-[(1-carbamoyl-1H-indol-3-yl)amid]-3-(S)-cyclohex-2-enylamid,
    (1R,3S,5R)-2-Azabicyclo[3.1.0]hexan-2,3-dicarbonsäure-2-[(1-carbamoyl-1H-indol-3-yl)amid]-3-{[(1S,3R)-3-(2,2,2-trifluorethoxy)cyclohexyl]amid},
    (1R,3S,5R)-2-Azabicyclo[3.1.0]hexan-2,3-dicarbonsäure-2-[(1-carbamoyl-1H-indol-3-yl)amid]-3-{[(1R,3S)-3-(2,2,2-trifluorethoxy)cyclohexyl]amid},
    (1R,3S,5R)-2-Azabicyclo[3.1.0]hexan-2,3-dicarbonsäure-2-[(1-carbamoyl-1H-indol-3-yl)amid]-3-{[(1S,3S)-3-(2,2,2-trifluorethoxy)cyclohexyl]amid},
    (1R,3S,5R)-2-Azabicyclo[3.1.0]hexan-2,3-dicarbonsäure-2-[(1-carbamoyl-1H-indol-3-yl)amid]-3-{[(1R,3R)-3-(2,2,2-trifluorethoxy)cyclohexyl]amid},
    (1R,3S,5R)-2-Azabicyclo[3.1.0]hexan-2,3-dicarbonsäure-2-[(1-carbamoyl-1H-indol-3-yl)amid]-3-[((1R,3S)-3-methoxycyclohexyl)amid],
    (1R,3S,5R)-2-Azabicyclo[3.1.0]hexan-2,3-dicarbonsäure-2-[(1-carbamoyl-1H-indol-3-yl)amid]-3-[((R)-3,3-dimethylcyclohexyl)amid],
    (1R,3S,5R)-2-Azabicyclo[3.1.0]hexan-2,3-dicarbonsäure-2-[(1-carbamoyl-1H-indol-3-yl)amid]-3-[((1R,3S)-3-ethylcyclohexyl)amid],
    (1R,3S,5R)-2-Azabicyclo[3.1.0]hexan-2,3-dicarbonsäure-2-[(1-carbamoyl-1H-indol-3-yl)amid]-3-[((1S,3R)-3-ethylcyclohexyl)amid],
    (1R,3S,5R)-2-Azabicyclo[3.1.0]hexan-2,3-dicarbonsäure-2-[(1-carbamoyl-1H-indol-3-yl)amid]-3-[((1R,3S)-3-methylcyclohexyl)amid],
    (1R,3S,5R)-2-Azabicyclo[3.1.0]hexan-2,3-dicarbonsäure-2-[(1-carbamoyl-1H-indol-3-yl)amid]-3-[((1R,3S)-3-trifluormethylcyclohexyl)amid],
    (2S,4R)-4-Fluorpyrrolidin-1,2-dicarbonsäure-1-[(1-carbamoyl-1H-indol-3-yl)amid]-2-[((R)-3,3-dimethylcyclohexyl)amid],
    1-{2-[(1R,3S,5R)-3-(3,3-Dimethylpiperidin-1-ylcarbamoyl)-2-azabicyclo[3.1.0]hex-2-yl]-2-oxoethyl}-6-methyl-1H-indazol-3-carbonsäureamid,
    1-{2-[(1R,3S,5R)-3-(3,3-Dimethylpiperidin-1-ylcarbamoyl)-2-azabicyclo[3.1.0]hex-2-yl]-2-oxoethyl}-5-methyl-1H-pyrazolo[3,4-c]pyridin-3-carbonsäureamid,
    (1R,3S,5R)-2-{2-[3-Acetyl-5-(pyrimidin-2-ylmethoxy)indazol-1-yl]acetyl}-2-azabicyclo[3.1.0]hexan-3-carbonsäure-(3,3-dimethyl-piperidin-1-yl)amid,
    (1R,3S,5R)-2-[2-(3-Acetylpyrazolo[3,4-c]pyridin-1-yl)acetyl]-2-azabicyclo[3.1.0]hexan-3-carbonsäure-(3-hydroxy-3-trifluormethylcyclohexyl)amid,
    (1R,3S,5R)-2-[2-(3-Acetylindazol-1-yl)acetyl]-2-azabicyclo[3.1.0]hexan-3-carbonsäure-(trans-3-trifluormethoxycyclohexyl)amid,
    1-{2-Oxo-2-[(1R,3S,5R)-3-(trans-3-trifluormethoxycyclohexylcarbamoyl)-2-azabicyclo[3.1.0]hex-2-yl]ethyl}-1H-indazol-3-carbonsäureamid,
    1-12-[(1R,3S,5R)-3-(3-Hydroxy-3-trifluormethylcyclohexylcarbamoyl)-2-azabicyclo[3.1.0]hex-2-yl]-2-oxoethyl}-1H-pyrazolo[3,4-c]pyridin-3-carbonsäureamid,
    1-{2-[(1R,3S,5R)-3-(2,2-Difluorcyclohexylcarbamoyl)-2-azabicyclo[3.1.0]hex-2-yl]-2-oxoethyl}-1H-pyrazolo[3,4-c]pyridin-3-carbonsäureamid,
    (1R,3S,5R)-2-{2-[3-Acetyl-5-(pyrimidin-2-ylmethoxy)indazol-1-yl]acetyl}-2-azabicyclo[3.1.0]hexan-3-carbonsäure-((S)-2,2-difluorcyclohexyl)amid,
    (1R,3S,5R)-2-{2-[3-Acetyl-5-(pyrimidin-2-ylmethoxy)indazol-1-yl]acetyl}-2-azabicyclo[3.1.0]hexan-3-carbonsäure-((R)-2,2-difluorcyclohexyl)amid,
    (1R,3S,5R)-2-{2-[3-Acetyl-5-(pyrimidin-2-ylmethoxy)indazol-1-yl]acetyl}-2-azabicyclo[3.1.0]hexan-3-carbonsäure-(2-fluorcyclohex-2-enyl)amid,
    1-{2-[(1R,3S,5R)-3-(3-Methoxy-3-trifluormethylcyclohexylcarbamoyl)-2-azabicyclo[3.1.0]hex-2-yl]-2-oxoethyl}-1H-indazol-3-carbonsäureamid,
    1-{2-[(1R,3S,5R)-3-(3-Methoxy-3-trifluormethylcyclohexylcarbamoyl)-2-azabicyclo[3.1.0]hex-2-yl]-2-oxoethyl}-1H-indazol-3-carbonsäureamid,
    1-{2-Oxo-2-[(1R,3S,5R)-3-((1R,3S)-3-trifluormethylcyclohexylcarbamoyl)-2-azabicyclo[3.1.0]hex-2-yl]ethyl}-1H-pyrazolo[3,4-c]pyridin-3-carbonsäureamid,
    (1R,3S,SR)-2-[2-(3-Acetylindazol-1-yl)acetyl]-2-azabicyclo[3.1.0]hexan-3-carbonsäure-((1S,3S)-3-methoxycyclohexyl)amid,
    (1R,3S,5R)-2-[2-(3-Acetylindazol-1-yl)acetyl]-2-azabicyclo[3.1.0]hexan-3-carbonsäure-((1R,3R)-3-methoxycyclohexyl)amid,
    (1R,3S,5R)-2-[2-(3-Acetylindazol-1-yl)acetyl]-2-azabicyclo[3.1.0]hexan-3-carbonsäure-((1S,3R)-3-methoxycyclohexyl)amid,
    (1R,3S,5R)-2-[2-(3-Acetylindazol-1-yl)acetyl]-2-azabicyclo[3.1.0]hexan-3-carbonsäure-((1R,3S)-3-methoxycyclohexyl)amid,
    1-{2-[(1R,3S,5R)-3-((1R,3S)-3-Methoxycyclohexylcarbamoyl)-2-azabicyclo[3.1.0]hex-2-yl]-2-oxoethyl}-1H-indazol-3-carbonsäureamid,
    1-{2-[(1R,3S,5R)-3-((1R,3S)-3-Methylcyclohexylcarbamoyl)-2-azabicyclo[3.1.0]hex-2-yl]-2-oxoethyl}-1H-indazol-3-carbonsäureamid,
    1-{2-[(1R,3S,5R)-3-((1S,3R)-3-Methylcyclohexylcarbamoyl)-2-azabicyclo[3.1.0]hex-2-yl]-2-oxoethyl}-1H-indazol-3-carbonsäureamid,
    1-{2-Oxo-2-[(1R,3S,5R)-3-((2R,3S)-3-Trifluormethylcyclohexylcarbamoyl)-2-azabicyclo[3.1.0]hex-2-yl]ethyl}-1H-indazol-3-carbonsäureamid,
    5-Methyl-1-{2-oxo-2-[(1R,3S,5R)-3-((1R,3S)-3-trifluormethylcyclohexylcarbamoyl)-2-azabicyclo[3.1.0]hex-2-yl]ethyl}-1H-pyrazolo[3,4-c]pyridin-3-carbonsäureamid,
    1-{2-[(1R,3S,5R)-3-((1R,3S)-3-Methylcyclohexylcarbamoyl)-2-azabicyclo[3.1.0]hex-2-yl]-2-oxoethyl}-1H-pyrazolo[3,4-c]pyridin-3-carbonsäureamid,
    1-{2-[(1R,3S,5R)-3-(3,3-Difluorcyclopentylcarbamoyl)-2-azabicyclo[3.1.0]hex-2-yl]-2-oxoethyl}-1H-indazol-3-carbonsäureamid,
    1-{2-[(1R,3S,5R)-3-((S)-3,3-Dimethylcyclohexylcarbamoyl)-2-azabicyclo[3.1.0]hex-2-yl]-2-oxoethyl}-1H-indazol-3-carbonsäureamid,
    1-{2-[(1R,3S,5R)-3-((R)-3,3-Dimethylcyclohexylcarbamoyl)-2-azabicyclo[3.1.0]hex-2-yl]-2-oxoethyl}-1H-indazol-3-carbonsäureamid,
    1-{2-[(1R,3S,5R)-3-((S)-3,3-Dimethylcyclohexylcarbamoyl)-2-azabicyclo[3.1.0]hex-2-yl]-2-oxoethyl}-1H-pyrazolo[3,4-c]pyridin-3-carbonsäureamid,
    1-{2-[(1R,3S,5R)-3-((R)-3,3-Dimethylcyclohexylcarbamoyl)-2-azabicyclo[3.1.0]hex-2-yl]-2-oxoethyl}-1H-pyrazolo[3,4-c]pyridin-3-carbonsäureamid,
    1-{2-Oxo-2-[(1R,3S,5R)-3-((S)-spiro[2.5]oct-5-ylcarbamoyl)-2-azabicyclo[3.1.0]hex-2-yl]ethyl}-1H-indazol-3-carbonsäureamid,
    1-{2-Oxo-2-[(1R,3S,5R)-3-((R)-spiro[2.5]oct-5-ylcarbamoyl)-2-azabicyclo[3.1.0]hex-2-yl]ethyl}-1H-indazol-3-carbonsäureamid,
    1-{2-[(1R,3S,5R)-3-((R)-3,3-Dimethylcyclohexylcarbamoyl)-2-azabicyclo[3.1.0]hex-2-yl]-2-oxoethyl}-5-methyl-1H-indazol-3-carbonsäureamid,
    1-{2-[(1R,3S,5R)-3-((R)-3,3-Dimethylcyclohexylcarbamoyl)-2-azabicyclo[3.1.0]hex-2-yl]-2-oxoethyll-6-fluor-1H-indazol-3-carbonsäureamid,
    1-{2-[(1R,3S,5R)-3-((R)-3,3-Dimethylcyclohexylcarbamoyl)-2-azabicyclo[3.1.0]hex-2-yl]-2-oxoethyl}-6-methyl-1H-indazol-3-carbonsäureamid,
    6-Chlor-1-{2-[(1R,3S,5R)-3-((R)-3,3-dimethylcyclohexylcarbamoyl)-2-azabicyclo[3.1.0]hex-2-yl]-2-oxoethyl}-1H-indazol-3-carbonsäureamid,
    1-{2-[(1R,3S,5R)-3-((R)-3,3-Dimethylcyclohexylcarbamoyl)-2-azabicyclo[3.1.0]hex-2-yl]-2-oxoethyl}-5-methyl-1H-pyrazolo[3,4-c]pyridin-3-carbonsäureamid,
    1-{2-[(1R,3S,5R)-3-((R)-3,3-Dimethylcyclohexylcarbamoyl)-2-azabicyclo[3.1.0]hex-2-yl]-2-oxoethyl}-5-ethyl-1H-pyrazolo[3,4-c]pyridin-3-carbonsäureamid,
    1-{2-[(1R,3S,5R)-3-((R)-3,3-Dimethylcyclohexylcarbamoyl)-2-azabicyclo[3.1.0]hex-2-yl]-2-oxoethyl}-7-methyl-1H-pyrazolo[3,4-c]pyridin-3-carbonsäureamid,
    (1R,3S,5R)-2-[2-(5-Acetylpyrrolo[2,3-c]pyridazin-7-yl)acetyl]-2-azabicyclo[3.1.0]hexan-3-carbonsäure-((R)-3,3-dimethylcyclohexyl)amid,
    1-{2-[(1R,3S,5R)-3-((S)-3,3-Dimethylcyclopentylcarbamoyl)-2-azabicyclo[3.1.0]hex-2-yl]-2-oxoethyl}-1H-pyrazolo[3,4-c]pyridin-3-carbonsäureamid,
    1-{2-[(1R,3S,5R)-3-((R)-3,3-Dimethylcyclopentylcarbamoyl)-2-azabicyclo[3.1.0]hex-2-yl]-2-oxoethyl}-1H-pyrazolo[3,4-c]pyridin-3-carbonsäureamid,
    (1R,3S,5R)-2-{2-[3-Acetyl-5-(pyrimidin-2-ylmethoxy)indazol-1-yl]acetyl}-2-azabicyclo[3.1.0]hexan-3-carbonsäure-((1R,3R)-3-methoxycyclohexyl)amid,
    1-{2-[(2S,4R)-2-((S)-3,3-Dimethylcyclohexylcarbamoyl)-4-fluorpyrrolidin-1-yl]-2-oxoethyl}-1H-pyrazolo[3,4-c]pyridin-3-carbonsäureamid,
    1-{2-[(2S,4R)-2-((R)-3,3-Dimethylcyclohexylcarbamoyl)-4-fluorpyrrolidin-1-yl]-2-oxoethyl}-1H-pyrazolo[3,4-c]pyridin-3-carbonsäureamid,
    1-{2-[(1R,3S,5R)-3-((1S,3R)-3-Ethylcyclohexylcarbamoyl)-2-azabicyclo[3.1.0]hex-2-yl]-2-oxoethyl}-1H-pyrazolo[3,4-c]pyridin-3-carbonsäureamid,
    1-{2-[(1R,3S,5R)-3-((1R,3S)-3-Ethylcyclohexylcarbamoyl)-2-azabicyclo[3.1.0]hex-2-yl]-2-oxoethyl}-1H-pyrazolo[3,4-c]pyridin-3-carbonsäureamid,
    1-{2-[(1R,3S,5R)-3-(3-Methylcyclohex-2-enylcarbamoyl)-2-azabicyclo[3.1.0]hex-2-yl]-2-oxoethyl}-1H-indazol-3-carbonsäureamid,
    1-{2-Oxo-2-[(1R,3S,5R)-3-((S)-spiro[2.5]oct-5-ylcarbamoyl)-2-azabicyclo[3.1.0]hex-2-yl]ethyl}-1H-pyrazolo[3,4-c]pyridin-3-carbonsäureamid,
    1-{2-Oxo-2-[(1R,3S,5R)-3-((R)-spiro[2.5]oct-5-ylcarbamoyl)-2-azabicyclo[3.1.0]hex-2-yl]ethyl}-1H-pyrazolo[3,4-c]pyridin-3-carbonsäureamid,
    1-{2-[(1R,3S,5R)-3-((1S,3R)-3-Methylcyclopentylcarbamoyl)-2-azabicyclo[3.1.0]hex-2-yl]-2-oxoethyl}-1H-indazol-3-carbonsäureamid,
    1-{2-[(1R,3S,5R)-3-((1S,3S)-3-Methylcyclopentylcarbamoyl)-2-azabicyclo[3.1.0]hex-2-yl]-2-oxoethyl}-1H-indazol-3-carbonsäureamid,
    1-{2-[(1R,3S,5R)-3-((1R,3R)-3-Methylcyclopentylcarbamoyl)-2-azabicyclo[3.1.0]hex-2-yl]-2-oxoethyl}-1H-indazol-3-carbonsäureamid,
    1-{2-[(1R,3S,5R)-3-((1R,3S)-3-Methylcyclopentylcarbamoyl)-2-azabicyclo[3.1.0]hex-2-yl]-2-oxoethyl}-1H-indazol-3-carbonsäureamid,
    1-{2-[(2S,4R)-2-((R)-3,3-Dimethylcyclohexylcarbamoyl)-4-fluorpyrrolidin-1-yl]-2-oxoethyl}-5-ethyl-1H-pyrazolo[3,4-c]pyridin-3-carbonsäureamid,
    1-{2-[(2S,4R)-2-((R)-3,3-Dimethylcyclohexylcarbamoyl)-4-fluorpyrrolidin-1-yl]-2-oxoethyl}-1H-indazol-3-carbonsäureamid,
    1-{2-[(1R,3S,5R)-3-((1R,3S)-3-Ethylcyclohexylcarbamoyl)-2-azabicyclo[3.1.0]hex-2-yl]-2-oxoethyl}-5-methyl-1H-pyrazolo[3,4-c]pyridin-3-carbonsäureamid,
    1-{2-[(2S,3S,4S)-2-((R)-3,3-Dimethylcyclohexylcarbamoyl)-4-fluor-3-methoxypyrrolidin-1-yl]-2-oxoethyl}-1H-indazol-3-carbonsäureamid,
    1-{2-[(2S,3S,4S)-2-((S)-3,3-Dimethylcyclohexylcarbamoyl)-4-fluor-3-methoxypyrrolidin-1-yl]-2-oxoethyl}-1H-indazol-3-carbonsäureamid,
    1-{2-[(1R,2S,5S)-2-((R)-3,3-Dimethylcyclohexylcarbamoyl)-3-azabicyclo[3.1.0]hex-3-yl]-2-oxoethyl}-1H-pyrazolo[3,4-c]pyridin-3-carbonsäureamid,
    1-{2-[(1R,2S,5S)-2-((S)-3,3-Dimethylcyclohexylcarbamoyl)-3-azabicyclo[3.1.0]hex-3-yl]-2-oxoethyl}-1H-pyrazolo[3,4-c]pyridin-3-carbonsäureamid,
    1-{2-[(1R,2S,5S)-2-((R)-3,3-Dimethylcyclohexylcarbamoyl)-3-azabicyclo[3.1.0]hex-3-yl]-2-oxoethyl}-1H-indazol-3-carbonsäureamid,
    1-{2-[(1R,2S,5S)-2-((S)-3,3-Dimethylcyclohexylcarbamoyl)-3-azabicyclo[3.1.0]hex-3-yl]-2-oxoethyl}-1H-indazol-3-carbonsäureamid,
    (1R,3S,5R)-2-[2-(3-Acetylindazol-1-yl)acetyl]-2-azabicyclo[3.1.0]hexan-3-carbonsäure-((S)-3,3-dichlorcyclohexyl)amid,
    (1R,3S,5R)-2-[2-(3-Acetylindazol-1-yl)acetyl]-2-azabicyclo[3.1.0]hexan-3-carbonsäure-((R)-3,3-dichlorcyclohexyl)amid,
    1-{2-[(2S,4R)-4-Fluor-2-((S)-spiro[2.5]oct-5-ylcarbamoyl)pyrrolidin-1-yl]-2-oxoethyl}-1H-indazol-3-carbonsäureamid,
    1-{2-[(2S,4R)-4-Fluor-2-((R)-spiro[2.5]oct-5-ylcarbamoyl)pyrrolidin-1-yl]-2-oxoethyl}-1H-indazol-3-carbonsäureamid,
    (lR,3S,5R)-2-{2-[3-Acetyl-5-(pyrimidin-2-ylmethoxy)indazol-1-yl]acetyl}-2-azabicyclo[3.1.0]hexan-3-carbonsäure-((1R,3S)-3-methoxycyclohexyl)amid,
    (1R,3S,5R)-2-{2-[3-Acetyl-5-(pyrimidin-2-ylmethoxy)indazol-1-yl]acetyl}-2-azabicyclo[3.1.0]hexan-3-carbonsäure-((1R,3S)-3-trifluormethylcyclohexyl)amid,
    (1R,3S,5R)-2-{2-[3-Acetyl-5-(pyrimidin-2-ylmethoxy)indazol-1-yl]acetyl}-2-azabicyclo[3.1.0]hexan-3-carbonsäure-((1R,3S)-3-methylcyclohexyl)amid,
    (1R,3S,5R)-2-{2-[3-Acetyl-5-(pyrimidin-2-ylmethoxy)indazol-1-yl]acetyl}-2-azabicyclo[3.1.0]hexan-3-carbonsäure-((S)-3,3-dimethylcyclohexyl)amid,
    (1R,3S,5R)-2-{2-[3-Acetyl-5-(pyrimidin-2-ylmethoxy)indazol-1-yl]acetyl}-2-azabicyclo[3.1.0]hexan-3-carbonsäure-((R)-3,3-dimethylcyclohexyl)amid,
    (1R,3S,5R)-2-{2-[3-Acetyl-5-(pyrimidin-2-ylmethoxy)indazol-1-yl]acetyl}-2-azabicyclo[3.1.0]hexan-3-carbonsäure-((1R,3R)-3-methoxycyclopentyl)amid,
    (1R,3S,5R)-2-{2-[3-Acetyl-5-(pyrimidin-2-ylmethoxy)indazol-1-yl]acetyl}-2-azabicyclo[3.1.0]hexan-3-carbonsäure-((1S,3S)-3-methoxycyclopentyl)amid,
    (1R,3S,5R)-2-{2-[3-Acetyl-5-(pyrimidin-2-ylmethoxy)indazol-1-yl]acetyl}-2-azabicyclo[3.1.0]hexan-3-carbonsäure-((1S,3R)-3-methoxycyclopentyl)amid,
    (1R,3S,5R)-2-{2-[3-Acetyl-5-(pyrimidin-2-ylmethoxy)indazol-1-yl]acetyl}-2-azabicyclo[3.1.0]hexan-3-carbonsäure-((1R,3S)-3-methoxycyclopentyl)amid,
    (1R,3S,5R)-2-{2-[3-Acetyl-5-(pyrimidin-2-ylmethoxy)indazol-1-yl]acetyl}-2-azabicyclo[3.1.0]hexan-3-carbonsäure-(3,3-dimethylcyclobutyl)amid,
    (1R,3S,5R)-2-{2-[3-Acetyl-5-(pyrimidin-2-ylmethoxy)indazol-1-yl]acetyl}-2-azabicyclo[3.1.0]hexan-3-carbonsäure-(3,3-difluorcyclobutyl)amid,
    1-{2-[(1R,3S,5R)-3-((1S,5S)-5-Methoxy-3,3-dimethylcyclohexylcarbamoyl)-2-azabicyclo[3.1.0]hex-2-yl]-2-oxoethyl}-1H-indazol-3-carbonsäureamid,
    1-{2-[(1R,3S,5R)-3-((1R,5R)-5-Methoxy-3,3-dimethylcyclohexylcarbamoyl)-2-azabicyclo[3.1.0]hex-2-yl]-2-oxoethyl}-1H-indazol-3-carbonsäureamid,
    1-{2-[(1R,3S,5R)-3-(cis-5-Methoxy-3,3-dimethylcyclohexylcarbamoyl)-2-azabicyclo[3.1.0]hex-2-yl]-2-oxoethyl}-1H-indazol-3-carbonsäureamid,
    1-{2-[(1R,3S,5R)-3-((1S,5S)-5-Hydroxy-3,3-dimethylcyclohexylcarbamoyl)-2-azabicyclo[3.1.0]hex-2-yl]-2-oxoethyl}-1H-indazol-3-carbonsäureamid,
    1-{2-[(1R,3S,5R)-3-((1R,5R)-5-Hydroxy-3,3-dimethylcyclohexylcarbamoyl)-2-azabicyclo[3.1.0]hex-2-yl]-2-oxoethyl}-1H-indazol-3-carbonsäureamid,
    1-{2-[(1R,3S,5S)-3-(3,3-Dimethylcyclohexylcarbamoyl)-5-hydroxymethyl-2-azabicyclo[3.1.0]hex-2-yl]-2-oxothyl}-1H-indazol-3-carbonsäureamid,
    1-{2-[(1R,3S,5S)-3-((R)-3,3-Dimethylcyclohexylcarbamoyl)-5-hydroxymethyl-2-azabicyclo[3.1.0]hex-2-yl]-2-oxoethyl}-1H-indazol-3-carbonsäureamid,
    1-{2-[(1R,3S,5S)-3-((S)-3,3-Dimethylcyclohexylcarbamoyl)-5-hydroxymethyl-2-azabicyclo[3.1.0]hex-2-yl]-2-oxoethyl}-1H-indazol-3-carbonsäureamid,
    (1R,3S,5S)-2-[2-(3-Acetylpyrazolo[3,4-c]pyridin-1-yl)acetyl]-5-hydroxymethyl-2-azabicyclo[3.1.0]hexan-3-carbonsäure-(S)-spiro[2.5]oct-5-ylamid,
    (1R,3S,5S)-2-[2-(3-Acetylpyrazolo[3,4-c]pyridin-1-yl)acetyl]-5-hydroxymethyl-2-azabicyclo[3.1.0]hexan-3-carbonsäure-(R)-spiro[2.5]oct-5-ylamid,
    (1R,3S,5S)-2-[2-(3-Acetylpyrazolo[3,4-b]pyridin-1-yl)acetyl]-5-hydroxymethyl-2-azabicyclo[3.1.0]hexan-3-carbonsäure-((R)-3,3-dimethylcyclohexyl)amid,
    (1R,3S,5S)-2-[2-(3-Acetylpyrazolo[3,4-b]pyridin-1-yl)acetyl]-5-hydroxymethyl-2-azabicyclo[3.1.0]hexan-3-carbonsäure-((S)-3,3-dimethylcyclohexyl)amid,
    1-12-[(1R,3S,5S)-3-((1S,3R)-3-Ethylcyclohexylcarbamoyl)-5-hydroxymethyl-2-azabicyclo[3.1.0]hex-2-yl]-2-oxoethyl}-1H-indazol-3-carbonsäureamid,
    1-{2-[(1R,3S,5S)-3-((1S,3S)-3-Ethylcyclohexylcarbamoyl)-5-hydroxymethyl-2-azabicyclo[3.1.0]hex-2-yl]-2-oxoethyl}-1H-indazol-3-carbonsäureamid,
    1-12-[(1R,3S,5S)-3-((1R,3R)-3-Ethylcyclohexylcarbamoyl)-5-hydroxymethyl-2-azabicyclo[3.1.0]hex-2-yl]-2-oxoethyl}-1H-indazol-3-carbonsäureamid,
    1-12-[(1R,3S,5S)-3-((1R,3S)-3-Ethylcyclohexylcarbamoyl)-5-hydroxymethyl-2-azabicyclo[3.1.0]hex-2-yl]-2-oxoethyl}-1H-indazol-3-carbonsäureamid,
    (1R,3S,5S)-2-[2-(3-Acetylpyrazolo[3,4-c]pyridin-1-yl)acetyl]-5-hydroxymethyl-2-azabicyclo[3.1.0]hexan-3-carbonsäure-((R)-3,3-dimethylcyclohexyl)amid und
    (1R,3S,5S)-2-[2-(3-Acetylpyrazolo[3,4-c]pyridin-1-yl)acetyl]-5-hydroxymethyl-2-azabicyclo[3.1.0]hexan-3-carbonsäure-((S)-3,3-dimethylcyclohexyl)amid.
  2. Pharmazeutische Zusammensetzung, umfassend einen oder mehrere pharmazeutisch unbedenkliche Träger und eine therapeutisch wirksame Menge einer Verbindung nach Anspruch 1.
  3. Kombination, umfassend eine therapeutisch wirksame Menge der Verbindung nach Anspruch 1 und eines zweiten Therapeutikums.
  4. Verbindung nach Anspruch 1 zur Verwendung als Medikament.
  5. Verbindung nach Anspruch 1 zur Verwendung bei der Behandlung einer Erkrankung bzw. Krankheit, wobei die Krankheit bzw. Erkrankung ausgewählt ist aus der Gruppe bestehend aus altersbedingter Makuladegeneration, geografischer Atrophie, diabetischer Retinopathie, Uveitis, Retinitis pigmentosa, Makulaödem, Behcet-Uveitis, multifokaler Choroiditis, Vogt-Koyangi-Harada-Syndrom, Uveitis intermedia, Birdshot-Chorioretinopathie, sympathischer Ophthalmie, okulärem vernarbendem Pemphigoid, okulärem Pemphigus, nichtarteriitischer ischämischer optischer Neuropathie, postoperativer Entzündung, Zentralvenenthrombose, neurologischen Erkrankungen, multipler Sklerose, Schlaganfall, Guillain-Barre-Syndrom, traumatischer Hirnverletzung, Parkinson-Krankheit, Erkrankungen mit unangemessener oder unerwünschter Komplementaktivierung, Hämodialysekomplikationen, hyperakuter Allograftabstoßung, Xenograftabstoßung, Interleukin-2-induzierter Toxizität während einer IL-2-Therapie, entzündlichen Erkrankungen, Entzündung bei Autoimmunkrankheiten, Morbus Crohn, Atemnotsyndrom des Erwachsenen, Myokarditis, postischämischen Reperfusionsleiden, Herzinfarkt, Ballonangioplastie, Post-Pump-Syndrom bei kardiopulmonalem Bypass oder renalem Bypass, Atherosklerose, Hämodialyse, renaler Ischämie, Mesenterialarterienreperfusion nach Aortarekonstruktion, Infektionskrankheit oder Sepsis, Immunkomplexerkrankungen und Autoimmunkrankheiten, rheumatoider Arthritis, systemischem Lupus erythematodes (SLE), SLE-Nephritis, proliferativer Nephritis, Leberfibrose, hämolytischer Anämie, Myasthenia gravis, Geweberegeneration, Nervenregeneration, Dyspnoe, Hämoptyse, ARDS, Asthma, chronischer obstruktiver Lungenkrankheit (Chronic Obstructive Pulmonary Disease, COPD), Emphysem, Lungenembolien und - infarkten, Pneumonie, fibrogenen Staubkrankheiten, Lungenfibrose, Asthma, Allergie, Bronchokonstriktion, Hypersensibilitätspneumonitis, parasitischen Krankheiten, Goodpasture-Syndrom, pulmonaler Vaskulitis, pauciimmuner Vaskulitis, immunkomplexassoziierter Entzündung, Antiphospholipidsyndrom, Glomerulonephritis und Obesitas.
  6. Verbindung zur Verwendung nach Anspruch 5, wobei es sich bei der Krankheit bzw. Erkrankung um altersbedingte Makuladegeneration handelt.
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US20150148349A1 (en) 2015-05-28
CN104640855A (zh) 2015-05-20
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WO2014002058A3 (en) 2014-03-20
CN104640855B (zh) 2017-08-29
US9487483B2 (en) 2016-11-08
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JP2015522008A (ja) 2015-08-03
EP2867227A2 (de) 2015-05-06

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